Long-Term Toxicity of Immunosuppressive Therapy (2024)

TABLE 97-1

Standard Incidence Ratio for Malignancies in Liver Transplant Recipients

From Chandok N, Watt KD. Burden of de novo malignancy in the liver transplant recipient. Liver Transpl. 2012;18(11):1281

Posttransplantation Lymphoproliferative Disorder

More specific to the transplant population is the collection of lymphoid malignancies known as posttransplantation lymphoproliferative disorder (PTLD). This was the single most common type of cancer reported among liver transplant recipients in the recent review by Sampaio etal.2 PTLD differs from lymphomas seen in immunocompetent patients in that it may present outside of nodal tissue, tends to arise (and regress) rapidly, and is frequently driven by Epstein-Barr virus (EBV). Indeed, the greatest risk for PTLD is seen in EBV-seronegative patients who receive an EBV-seropositive organ. Thus PTLD may reasonably be considered an infectious disease risk with oncological sequelae rather than a case of direct oncological transformation. Accordingly, PTLD responds to reduction or withdrawal of immunosuppression in approximately 50% of affected individuals, making prompt and aggressive reduction of immunosuppression the first therapeutic maneuver upon diagnosis. In a long-term follow-up study of liver transplant patients at the Mayo Clinic in Rochester, Minnesota, the overall incidence of PTLD was 3.1% with EBV-negative disease predominating later after transplantation (Fig. 97-1).3

PTLD may occur anytime after transplant and usually presents with the typical viral prodrome of malaise, fever, and weight loss. Laboratory findings typically include an elevated l-lactate dehydrogenase level and EBV viremia. Graft involvement and central nervous system invasion, as well as multiple site involvement, are poor prognostic factors. Diagnosis requires biopsy-proven disease of the affected organ or lymph node. Oncological evaluation is required. An elevated EBV level on polymerase chain reaction, although not diagnostic, may be suggestive of PTLD and can be used to gauge its course. Treatment consists primarily of immunosuppression withdrawal, allowing the patient to mount a response against EBV and PTLD. In addition, antiviral directed therapy (e.g., ganciclovir) is started. When withdrawal is insufficient, adjuvant therapies, including irradiation and chemotherapy, may be considered, typically CHOP (cyclophosphamide, hydroxydaunomycin [doxorubicin], Oncovin [vincristine], and prednisone)-based regimens.

Rituximab, an anti-CD20 antibody, may lead to remission in certain cases of PTLD. Early-onset PTLD is frequently B cell in origin and CD20 positive, making Rituximab a viable option and an often-used adjuvant to standard chemotherapeutic agents. Late-onset PTLD is usually non-Hodgkin’s lymphoma and is not viral related.

TABLE 97-2

Common Infections in Solid Organ Transplant Recipients

From Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med. 2007;357(25):2606.

TABLE 97-3

Side Effects of Long-Term Corticosteroid Use

Endocrine

A well-known complication of long-term CS use is diabetes, which occurs in up to 40% of adult liver transplant recipients.7 CS-induced diabetes results in impaired glucose metabolism through increased insulin resistance. The mechanisms resulting in hyperglycemia include (1) a reduction in insulin production, (2) an increase in gluconeogenesis, (3) a decrease in peripheral glucose utilization, and (4) reduced glycogen synthesis. These effects are thought to be dose dependent, because reduced doses of CS have been shown to decrease insulin resistance.8 In addition, CSs enhance appetite, particularly for sweetened foods. As will be described later, calcineurin inhibitors (CNIs) contribute significantly to the development of posttransplantation diabetes mellitus (PTDM). Even though many programs have employed steroid avoidance or low-maintenance-dose CS protocols, PTDM remains a considerable problem. Thus one can extrapolate that PTDM is primarily due to the CNI.

The prevalence of dyslipidemia has been documented in up to 45% of liver transplant recipients.9 The mechanism or mechanisms leading to dyslipidemia are not clear but may be due to steroid-induced insulin resistance, which leads to increased levels of very-low-density lipoprotein (VLDL), triglycerides, and low-density lipoprotein (LDL). Lipogenesis may also be pronounced with CS use.

Cardiovascular

The endocrine complications just described (diabetes and dyslipidemia) increase the risk for cardiovascular events after transplantation. Another risk factor contributing to cardiac disease is hypertension. The mechanisms involved in causing an increase in blood pressure include (1) sodium and water retention in the distal nephron, (2) upregulation of receptors present on vascular smooth muscle, and (3) contributions involving pathways in the central nervous system, adipose tissue, and liver.10

Liver transplant recipients not previously diagnosed with hypertension may develop elevated blood pressure after transplantation. While no one medication can tackle all the mechanisms listed earlier, use of a calcium channel blocker and a diuretic (if merited) may prove effective as first-line therapy.

Musculoskeletal

The musculoskeletal complications of prolonged CS use are devastating. CS use is the leading cause of secondary (drug-induced) osteoporosis. Bone metabolism is affected through several pathways, mainly by (1) suppressing osteoblast proliferation and activity, (2) stimulating osteoclasts to induce bone resorption, (3) decreasing calcium absorption in the GI tract, and (4) increasing urinary calcium excretion.11 Bone loss due to CS use is greater in trabecular bone compared to cortical bone; thus the risk for fractures is greatest in the vertebral bodies, ribs, and femoral heads.

In liver transplant candidates the risk for osteoporosis and fractures is already elevated due to the effects of chronic disease, medications, and immobilization. Other common risk factors seen in liver transplant recipients include advanced age, increased body weight, and female sex, specifically postmenopausal women.

The incidence of fractures in transplant recipients is highest within the first 6 to 12 months after transplantation, with documented rates ranging from 24% to 65%.12 Fractures may even occur with doses as low as 2.5 mg of prednisone daily.13 Fortunately, the risk for bone loss is dose dependent, and the likelihood of fracture rapidly decreases after CSs are discontinued. Measures to prevent and manage osteoporosis will be discussed elsewhere in this textbook. At our center all posttransplantation patients are placed on supplemental calcium and vitamin D.

Because of the numerous side effects of CSs, attempts have been made to reduce or remove CSs from standard posttransplantation immunosuppressive regimens. At our center, steroids are eliminated within 2 weeks after transplantation in the majority of our recipients, except for those with autoimmune etiologies (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis), where complete elimination may result in an early flare of the underlying disease. Eliminating CSs completely from our armamentarium is unlikely. Although linked to many long-term effects, CSs are effective agents that have resulted in the success of transplantation.

Neurotoxicity

Principally considered an immediate side effect of CNIs, neurotoxicity may become apparent months or years after initiation.14 In addition, one must be cognizant of this side effect when converting patients onto CNI immunosuppression or when anticipating a rise in CNI levels in the face of drug interactions. Thus this potentially harmful consequence merits attention here.

The frequency of CNI-induced neurotoxicity has been reported to range from 7% to 32%15., 16. and is generally more common and severe with Tac than with CyA.17 The mildest forms of neurotoxicity are headaches, migraines, or a fine tremor. Not typically responsive to acetaminophen, headaches and migraines are generally responsive to sumatriptan (Imitrex). These events are usually dose related and reversible with reduction of the CNI. For symptoms that persist, conversion off Tac to CyA or another agent may be necessary.

On the opposite end of the spectrum, severe side effects include cognitive changes (psychosis, hallucinations), posturing (opisthotonus), seizure activity, and coma. The most severe consequence of CNI neurotoxicity is posterior reversible encephalopathy syndrome (PRES), a condition consisting of severe neurological deficits with magnetic resonance imaging findings of cortical and subcortical cytotoxic edema. Whether CNI trough levels are elevated or not, the CNI should be discontinued immediately. Furthermore, for the more severe neurological complications, there is no correlation with CNI levels, suggesting an idiosyncratic response.18 Serum magnesium monitoring and supplementation are recommended. Potentially fatal in the most extreme circ*mstances, CNI-induced neurotoxicity is generally reversible, but functional recovery may require months.

Renal Dysfunction

CNI-associated nephrotoxicity was described early, with the use of CyA in bone marrow transplantation.19 Not surprisingly, the administered doses of CyA were many times greater (15 mg/kg) than what is recommended today. Further studies in animal and human biopsy tissue confirmed the various pathological changes in the nephron caused by CyA.20., 21. Striking was the vasculopathy of the afferent arterioles, resulting in intimal fibrosis, eventual glomerular collapse, and the nephropathy seen today (Fig. 97-2).20 For practical purposes, Tac and CyA are equally nephrotoxic.

The development and severity of chronic kidney disease after solid organ transplantation was uncovered in two landmark papers. First, Gonwa etal22 demonstrated a 40% decline in renal function (by measured glomerular filtration rate) at 3 months in liver transplant recipients without renal dysfunction. Next, Ojo etal23 found the cumulative incidence of chronic renal failure in liver transplant recipients to be nearly 20% at 5 years. Since then a major focus in the field of transplantation has been to identify and address the causes of perioperative renal dysfunction. Topping this list is the nephrotoxic effects of CNI, which has been the principal stimulus for the development of new immunosuppressive agents.

Metabolic Syndrome

Other recognized long-term side effects associated with CNIs are posttransplantation hyperlipidemia, diabetes, and hypertension, all of which are elements of the metabolic syndrome. Of course, there are other factors that predispose transplant recipients to these risks, including race, age, unrecognized preexisting disease, body mass index, and CS use, to name a few. These consequences ultimately contribute to the increasing cardiovascular morbidity and mortality seen long-term. Thus early screening and interventions may aid in reducing these risks.

The prevalence of hyperlipidemia after transplantation is upwards of 50% in multiple studies.24., 25., 26. CNIs have been associated with this side effect, as have CSs. Postulated mechanisms for CNI-related hyperlipidemia include (1) binding to the LDL receptor (increasing serum LDL), (2) decreased activity of lipoprotein lipase (increasing serum VLDL and LDL), and (3) inhibition of bile acid synthesis leading to increases in cholesterol.27

PTDM is seen in upwards of 40% of liver transplant recipients. CNIs cause PTDM by inhibiting insulin secretion by pancreatic β-islet cells. Tac is significantly more diabetogenic than CyA. In a meta-analysis comparing the effects of Tac and CyA in renal transplantation, Tac-treated patients had a significantly increased risk for new-onset PTDM compared to CyA-treated patients (relative risk, 1.85 at 1 year), and further increased risk with increasing Tac trough concentrations.28 Also, African Americans are at increased risk relative to whites. The combination of CNI and CS further exacerbates the predilection to glucose intolerance.

The prevalence of posttransplantation hypertension is also high in patients taking CNI. In one early study of liver transplant recipients taking either CyA or Tac, elevated blood pressure (>140/90 mm Hg) was seen in up to 75% of patients during the first few months after liver transplant.29 The modern incidence is likely lower because reduced doses of the CNI are used and CS use has been minimized. Nonetheless, treating hypertension after liver transplantation is the norm. Mechanisms causing CNI-induced hypertension include sodium retention, decreased production of vasodilating substances (nitric oxide and prostacyclin), and renal vasoconstriction.30

Other undesirable outcomes associated with CyA include acne, hirsutism, and gingival hyperplasia. These unfavorable aesthetic results may lead to a patient’s request to change CyA to Tac, which has a lesser risk for these consequences. Table 97-4outlines some of the more common side effects of CNI.

Dyslipidemia

In a review of randomized controlled trials on the subject, increases in cholesterol and triglyceride levels were shown to be associated with mTOR inhibitor use.33 Roughly twice as many recipients on mTOR inhibitors were treated with lipid-lowering agents. The cause for the dyslipidemia may be increased plasma levels of apolipoprotein B-100, resulting in elevated VLDL and LDL levels.34 Interestingly, whether this translates into increased atherosclerotic disease is not supported, because SRL has been shown to reduce atherosclerosis in an animal model.35 In a recent study by McKenna etal,36 liver transplant recipients on de novo SRL had similar incidences of cardiovascular events (e.g., myocardial infarction, stroke) after transplant as the control patients (never on SRL) despite statistically higher total cholesterol and triglyceride levels and a significantly higher Framingham risk score in the SRL cohort. Thus, despite causing dyslipidemias, SRL may have cardioprotective properties stemming from immune modulation of various pathways causing atherosclerosis.

Proteinuria

Although mTOR inhibitors do not cause any renal tubular dysfunction, they are associated with a higher incidence of proteinuria, generally a marker of chronic renal disease. This has been documented in kidney transplantation not only for de novo use, but also for early and late conversions after transplantation. The long-term implications of proteinuria in de novo use are unknown; however, among kidney transplant patients converted to SRL, Gutierrez etal37 found that patients with baseline proteinuria greater than 0.8 mg/dL along with a greater degree of renal insufficiency were at higher risk for further proteinuria and progressive renal dysfunction. Although not mentioned as a potential complication in the early trials for SRL, proteinuria was clearly documented when EVR was approved for kidney transplantation. The mechanism by which SRL causes or accentuates proteinuria is not yet defined. However, angiotensin-converting enzyme inhibitors and statins have been shown to reduce proteinuria in patients with renal dysfunction, with one study suggesting that these therapies are effective in limiting mTOR inhibitor–induced proteinuria.38

Patients being considered for SRL conversion should be assessed for preexisting proteinuria with a 24-hour urine collection. If the proteinuria is less than 300 mg/day, the renal dysfunction can be reversed through conversion of CNI to SRL. In those patients with established proteinuria of more than 300 mg/day, a conversion to SRL may exacerbate the existing proteinuria and accelerate renal dysfunction. Therefore these patients should be maintained on low levels of CNI. Late conversion (more than 2 years after transplantation) to SRL usually does not improve renal function but instead may exacerbate renal dysfunction.

Wound Complications

Patients taking mTOR inhibitors have a known increased risk for developing wound complications. The same antiproliferative mechanism that is thought to produce their beneficial oncological effects (e.g., against hepatocellular carcinoma) may also account for their poor wound-healing properties (by limiting fibroblast proliferation). Examples of wound complications include tracheal dehiscence in lung transplant recipients and an increased occurrence of lymphoceles in kidney transplant recipients.39., 40.

The literature assessing wound complications in liver transplant is not plentiful. Early experiences with SRL in liver transplantation confirmed that wound infections and dehiscences were more frequent.41., 42. However, initial trials with SRL used higher doses and trough levels than is generally used today. In one randomized controlled trial looking at the efficacy of EVR, there was a trend for more incisional hernias in the EVR arm (46% versus 27%, P = .16).43 In the recent PROTECT study on EVR in liver transplantation, no increase in wound-healing problems was noted.44

At the Baylor Simmons Transplant Institute we have vast experience using SRL in our liver transplant patients, with both de novo and conversion therapy. The rate of wound complications, including the development of incisional hernias, is anecdotally high (and currently being reviewed). For the transplant patient on de novo SRL, incisions are monitored carefully. An incision-line wound vacuum-assisted closure can assist with wound healing. For long-term recipients who have developed an incisional hernia and are taking SRL, precaution is taken before herniorrhaphy by converting the patient off SRL and onto a CNI for 2 weeks before repair, with reinstitution of SRL (and discontinuation of the CNI) at least 4 weeks after repair or until the wound heals completely. This conversion can be carried out with minimal concern for rejection. (Of note, conversion back to SRL requires the readdition of the secondary agent [e.g., mycophenolate or AZA] because SRL monotherapy is not practiced at our center.)

Oral Ulcers

Oral ulcers are a common side effect of mTOR inhibitors, affecting up to 40% of patients taking these medications.45., 46. They can also occur late after long-term use. Often mistaken for oral herpes simplex virus infections, these ulcers can be painful and are one of the most common reasons for discontinuation. Current management involves a topical steroid combined with a dental paste (e.g., Kenalog in Orabase) applied directly to the ulcer. Secondarily, the dose of the mTOR inhibitor can be reduced.

Another troublesome consequence seen with the use of mTOR inhibitors is bone marrow suppression (namely leukopenia and anemia), which may be ameliorated via dose reduction and treatment (i.e., filgrastim [Neupogen] injection, iron supplementation, and transfusion). SRL is also associated with an atypical noninfectious pneumonitis, which is rarely seen today, in approximately 1% of patients. This side effect was more frequently observed with higher doses of SRL during its initial experience. Once recognized, it can be treated by SRL discontinuation.

Pearls & Pitfalls

• •

  Knowledge and understanding of the long-term side effects of immunosuppression can lead to the early detection and treatment of potential complications.

• •

  Identification and treatment of posttransplantation lymphoproliferative disorder require suspicion of diagnosis, prompt reduction of immunosuppressive medications, and early oncological evaluation.

• •

  Skin cancer is the most common malignancy after liver transplantation. Precautions such as sunscreen, protective cover, and dermatological evaluation should be followed.

• •

  Prolonged corticosteroid and calcineurin inhibitor use contribute to increased cardiovascular morbidity (e.g., hypertension, hyperlipidemia, and hyperglycemia) and mortality. Management of these issues should be incorporated into all patients’ general maintenance plans early to mitigate their long-term effects.

• •

  Despite their established nephrotoxicity and risk for renal failure, calcineurin inhibitors (tacrolimus and cyclosporine) remain the gold standard oral immunosuppressive agents.

• •

  तammalian target of rapamycin (mTOR) inhibitors should be considered early for conversion therapy in recipients with renal dysfunction. Dyslipidemia, proteinuria, and wound complications are their well-known side effects.

• •

  Thymoglobulin and, to a lesser degree, alemtuzumab are associated with infusion-related symptoms collectively referred to as cytokine release syndrome (fever, chest pain, dyspnea, tachycardia) which require appropriate premedication and vigilance during administration, particularly in patients with limited cardiovascular reserve.

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